In contrast with melanoma, lung cancer, and kidney cancer, immune checkpoint inhibitor therapy has been disappointing in prostate cancer thus far. Because of success in treating other tumor types, interest remains high in exploring the effect of immunotherapy with checkpoint inhibition in prostate cancer, even though it is considered a tumor with an immunologically “cold” microenvironment.

The phase II CheckMate 650 study, presented at the 2019 Genitourinary Cancers Symposium,¹ showed that combination therapy with nivolumab plus ipilimumab had activity in patients with advanced metastatic castration-resistant prostate cancer, with greater activity in patients who had not received prior chemotherapy compared with those who had been previously treated with chemotherapy. The main drawback of treatment was toxicity, since just 24% to 33% of patients were able to receive the full planned 4 cycles of ipilimumab and nivolumab.

In a malignancy where immune checkpoint monotherapy has shown limited activity, nivolumab plus ipilimumab demonstrated antitumor activity in patients with metastatic castration-resistant prostate cancer.

— Padmanee Sharma, MD, PhD

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“In a malignancy where immune checkpoint monotherapy has shown limited activity, nivolumab plus ipilimumab demonstrated antitumor activity in patients with metastatic castration-resistant prostate cancer,” said lead author Padmanee Sharma, MD, PhD, Professor of Genitourinary Medical Oncology and Immunology, at The University of Texas MD Anderson Cancer Center, Houston.

“Deep and durable objective responses, as well as falls in prostate-specific antigen (PSA) levels (< 2 ng/mL], were observed in a subgroup of patients,” Dr. Sharma told listeners. “Although the numbers were small, preliminary data suggest that biomarkers (ie, tumor mutational burden, programmed cell death ligand 1 [PD-L1] ≥ 1%, homologous recombination repair defects, and DNA damage and repair) may have a role in identifying patients with metastatic castration-resistant prostate cancer likely to respond to immunotherapy,” Dr. Sharma told listeners. “Further study of the combination is warranted.”

Study Details

The CheckMate 650 study enrolled 90 patients with metastatic castration-resistant prostate cancer divided into 2 cohorts based on previous treatment: cohort 1 included symptomatic/minimally symptomatic patients whose disease progressed after treatment with second-generation hormone therapy and had not received chemotherapy for metastatic castration-resistant prostate cancer; cohort 2 included patients who had disease progression after cytotoxic chemotherapy. All patients were continued on androgen-deprivation therapy. More than 50% of patients received previous treatment with either abiraterone acetate plus prednisone or enzalutamide.

Patients enrolled in the trial were slated to receive treatment with nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for 4 doses, followed by maintenance therapy with nivolumab at 480 mg every 4 weeks. Treatment was continued until disease progression or unacceptable toxicity, and patients could be treated beyond disease progression if they had sustained clinical benefit.

At baseline, the median age of patients was 69 years in cohort 1 and 65 years in cohort 2, and the median time from diagnosis was 7.1 years in cohort 1 and 7.5 years in cohort 2.

Efficacy and Exposure

Greater benefit from the immunotherapy combination was reported in patients who had not received prior chemotherapy (cohort 1), although responses were also seen in cohort 2. The objective response rate was of 25% in cohort 1 and 10% in cohort 2. A total of 2 complete responses were observed in each cohort, and partial responses were seen in 6 patients in cohort 1 and 1 patient in cohort 2. The median time to response was 1.9 months in the first cohort and 2.1 months in cohort 2. Additionally, 13 patients achieved stable disease in cohort 1 and 11 patients in cohort 2.

A total of 33.3% of patients in cohort 1 and 24.4% in cohort 2 were able to receive all 4 doses of the planned combination therapy. A total of 14 and 9 patients, respectively, were able to receive maintenance nivolumab.

The median radiographic progression-free survival was 5.5 months in cohort 1 and 3.8 months in cohort 2. The median overall survival was 19 months in cohort 1 and 15.2 months in cohort 2.

Potential Biomarker

Whole-exome sequencing of tumor samples was performed in 44 patients. In an exploratory analysis of biomarkers for response, higher tumor mutational burden (defined as above the median of 74.5 mutations per patient) appeared to be associated with response, with half of patients with higher tumor mutational burden achieving an objective response in both cohorts. Moreover, a significant association was seen between higher tumor mutational burden and longer radiographic progression-free survival (7.4 vs 2.4 months; P < .0001).

Patients with PD-L1 tumor expression (PD-L1 > 1%) as well as those with homologous repair homologous repair defects and/or DNA damage repair status also had numerically higher response rates, although the small size of the subgroups limits drawing any conclusions.

Toxicity

Almost all patients with prostate cancer experienced treatment-related adverse events of any grade. Grades 3 to 5 events were experienced by 42.2% of patients in cohort 1 and 53.3% of patients in cohort 2. Adverse events also caused about 51.1%of patients in cohorts 1 and 44.4% of patients in cohort 2 to stop therapy. Diarrhea, fatigue, skin rash, nausea, and hypothyroidism were the most common adverse events. Four treatment-related deaths occurred (two in each cohort).

To address toxicity, “the dose/schedule optimization will be important for patients with metastatic castration-resistant prostate cancer, given the number of patients not completing all four combination doses and discontinuing study treatment due to toxicity,” Dr. Sharma told the audience. ■

DISCLOSURE: The study was sponsored by Bristol-Myers Squibb. Dr. Sharma has stock and other ownership interests in BioAtla, Kite Pharma, Constellation Pharmaceuticals, Evelo Therapeutics, Jounce Therapeutics, Neon Therapeutics, and Oncolytics; has an immediate family member who has stock and other ownership interests in Kite Pharma and Jounce Therapeutics; is a consultant/advisor for GlaxoSmithKline, Bristol-Myers Squibb, Amgen AstraZeneca, Constellation Pharmaceuticals, Jounce Therapeutics, Kite Pharma, Evelo Therapeutics, Neon Therapeutics, Astellas Pharma, Oncolytics, Pieris Pharmaceuticals, BioAtla, Merck Sharp & Dohme, and EMD Sereno; has an immediate family member who is a consultant/advisor for Neon Therapeutics, EMD Sereno, Evelo Therapeutics, Kite Pharma, Jounce Therapeutics, Constellation Pharmaceuticals, AstraZeneca, Amgen, Bristol-Myers Squibb, and GlaxoSmithKline; has patents/royalties/other intellectual property with Jounce Therapeutics; and has an immediate family member who has patents/royalties/other intellectual property with Jounce Therapeutics, Bristol-Myers Squib, and Merck.

REFERENCE

1. Sharma P, Pachynski RK, Narayan V, et al: Initial results from a phase II study of nivolumab plus ipilimumab for the treatment of metastatic castration-resistant prostate cancer: CheckMate 650. 2019 Genitourinary Cancers Symposium. Abstract 142. Presented February 14, 2019.